Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions and multiple allergies, and isolated patient keratinocytes exhibit increased proallergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the 3 tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1–/– skin showed a delay in expression of adhesion/differentiation/ keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17–skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1–/– mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of 2 Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, and treatment with a targeted therapy significantly improved skin lesions in patients

Low fingertip temperature rebound measured by digital thermal monitoring strongly correlates with the presence and extent of coronary artery disease diagnosed by 64-slice multi-detector computed tomography

Previous studies showed strong correlations between low fingertip temperature rebound measured by digital thermal monitoring (DTM) during a 5 min arm-cuff induced reactive hyperemia and both the Framingham Risk Score (FRS), and coronary artery calcification (CAC) in asymptomatic populations. This study evaluates the correlation between DTM and coronary artery disease (CAD) measured by CT angiography (CTA) in symptomatic patients. It also investigates the correlation between CTA and a new index of neurovascular reactivity measured by DTM. 129 patients, age 63 ± 9 years, 68% male, underwent DTM, CAC and CTA. Adjusted DTM indices in the occluded arm were calculated: temperature rebound: aTR and area under the temperature curve aTMP-AUC. DTM neurovascular reactivity (NVR) index was measured based on increased fingertip temperature in the non-occluded arm. Obstructive CAD was defined as ≥50% luminal stenosis, and normal as no stenosis and CAC = 0. Baseline fingertip temperature was not different across the groups. However, all DTM indices of vascular and neurovascular reactivity significantly decreased from normal to non-obstructive to obstructive CAD [(aTR 1.77 ± 1.18 to 1.24 ± 1.14 to 0.94 ± 0.92) (P = 0.009), (aTMP-AUC: 355.6 ± 242.4 to 277.4 ± 182.4 to 184.4 ± 171.2) (P = 0.001), (NVR: 161.5 ± 147.4 to 77.6 ± 88.2 to 48.8 ± 63.8) (P = 0.015)]. After adjusting for risk factors, the odds ratio for obstructive CAD compared to normal in the lowest versus two upper tertiles of FRS, aTR, aTMP-AUC, and NVR were 2.41 (1.02–5.93), P = 0.05, 8.67 (2.6–9.4), P = 0.001, 11.62 (5.1–28.7), P = 0.001, and 3.58 (1.09–11.69), P = 0.01, respectively. DTM indices and FRS combined resulted in a ROC curve area of 0.88 for the prediction of obstructive CAD. In patients suspected of CAD, low fingertip temperature rebound measured by DTM significantly predicted CTA-diagnosed obstructive disease

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Global cardiometabolic risk profile in patients with hypertension: Results from the Turkish arm of the pan-European GOOD survey

Objectives: We evaluated the results of the Turkish arm of the GOOD survey which investigated the cardiometabolic risk profile and the control of blood pressure (BP) of adult hypertensive outpatients in 12 countries across Europe. Study design: A total of 218 hypertensive patients (139 females, 79 males; mean age 57.2±10.9 years) from Turkey were included in this pan-European survey. Blood pressure control (defined as BP <140/90 mmHg for nondiabetics and <130/80 mmHg for diabetics) and cardiometabolic risk factors such as diabetes mellitus, metabolic syndrome, obesity, sedentary lifestyle, and atherogenic dyslipidemia were evaluated in accordance with the 2003 ESH/ESC guidelines on management of hypertension. Results: Control of BP was achieved in only 21.6% of the patients diagnosed with hypertension for a mean duration of 7.7±5.4 years. The mean systolic and diastolic BPs were 144±21 mmHg and 88±14 mmHg, respectively. The most frequent concomitant disease was type 2 diabetes mellitus (66 patients, 30.3%). Patients with diabetes had a higher prevalence of metabolic syndrome compared to nondiabetics (78.8% vs. 48%, p<0.01). The absence of BP control was more pronounced among diabetics than in nondiabetics for systolic (77.3% vs. 63.8%) and diastolic (84.9% vs. 57.2%) pressures. Nearly half of the hypertensive patients had atherogenic dyslipidemia, but only 35.8% of them were treated with lipid lowering drugs. Conclusion: Despite appropriate treatment, poor BP control in Turkish hypertensive patients was associated with metabolic syndrome, diabetes, and undertreatment of atherogenic dyslipidemia. Therefore, more effective measures must be taken in the management of cardiovascular risk factors to improve BP control

Global cardiometabolic risk profile in patients with hypertension: Results from the Turkish arm of the pan-European GOOD survey

PubMed ID: 21200100Objectives: We evaluated the results of the Turkish arm of the GOOD survey which investigated the cardiometabolic risk profile and the control of blood pressure (BP) of adult hypertensive outpatients in 12 countries across Europe. Study design: A total of 218 hypertensive patients (139 females, 79 males; mean age 57.2±10.9 years) from Turkey were included in this pan-European survey. Blood pressure control (defined as BP <140/90 mmHg for nondiabetics and <130/80 mmHg for diabetics) and cardiometabolic risk factors such as diabetes mellitus, metabolic syndrome, obesity, sedentary lifestyle, and atherogenic dyslipidemia were evaluated in accordance with the 2003 ESH/ESC guidelines on management of hypertension. Results: Control of BP was achieved in only 21.6% of the patients diagnosed with hypertension for a mean duration of 7.7±5.4 years. The mean systolic and diastolic BPs were 144±21 mmHg and 88±14 mmHg, respectively. The most frequent concomitant disease was type 2 diabetes mellitus (66 patients, 30.3%). Patients with diabetes had a higher prevalence of metabolic syndrome compared to nondiabetics (78.8% vs. 48%, p<0.01). The absence of BP control was more pronounced among diabetics than in nondiabetics for systolic (77.3% vs. 63.8%) and diastolic (84.9% vs. 57.2%) pressures. Nearly half of the hypertensive patients had atherogenic dyslipidemia, but only 35.8% of them were treated with lipid lowering drugs. Conclusion: Despite appropriate treatment, poor BP control in Turkish hypertensive patients was associated with metabolic syndrome, diabetes, and undertreatment of atherogenic dyslipidemia. Therefore, more effective measures must be taken in the management of cardiovascular risk factors to improve BP control